Filter for the Removal of Substances from Blood Products

ABSTRACT

A filter device for the depletion of the leukocyte content from blood products comprising: a porous element comprising at least one fibrous web having a pore size suitable for leukocyte removal (possibly the range for the pore size should be defined), said web comprising fibres of a hydrophobic polymer coated with a hydrophilic polymer suitable to enhance the CWST of said hydrophobic polymer, characterised in that said web further includes adsorbent particles having a mean diameter lower than 30 μm, said particles being bonded to said fibres by means of said hydrophilic polymer coating said fibres.

The present invention relates to a filter for the removal of leukocytesfrom blood or blood components and more particularly, to a leukocytefilter adapted for use in the blood purification devices, such as bloodbag systems which are conventionally used for the separation of wholeblood into leukocyte depleted hemocomponents.

The blood filters, to which the present invention relates, typicallycomprise a housing with inlet and outlet ports and at least a porouselement, within the housing, interposed between the inlet and outletport.

The porous element usually consists of a web which may be formed by oneor more layers of filtering material, typically a non-woven fabric.

According to the prior art, the porous elements can be produced from anymaterial compatible with blood, which is capable of forming fibresincluding natural or synthetic fibres.

The preferred materials are synthetic polymers, such as particularlypolyolefins, polyesters and polyamides.

Fibrous leukocyte filters are well-known in the prior art and aredescribed e.g. in EP-A-0 313 348 and EP-A-0 397 403.

Preferred materials for use in leukocyte filters are synthetic resins,which are adapted to be processed into very fine fibres (with a diameterpreferably lower than 3 μm) by melt-blowing.

The currently used preferred material is polybutyleneterephthalate(PBT). The surface properties of the employed fibre material can bemodified to increase its wettability or its Critical Wetting SurfaceTension (CWST), which is a measure of the hydrophilicity of thematerial.

To this end, fibres of a hydrophobic resin, such as PBT, have beencoated with a more hydrophilic polymer, such as particularly hydrophilicacrylic polymers or copolymers or hydrophilic polyurethanes.

The polymeric material used for the fibres can also be rendered morehydrophilic by surface grafting the polymeric material, particularlyPBT, with compounds containing an ethylenically unsaturated group, suchas an acrylic moiety combined with hydroxyl groups or methylacrylate ormethylmethacrylate and combinations thereof, as described in EP-A-0 313348.

In general, a filter with a higher hydrophilicity is enhancing therecovery of platelets, as described in U.S. Pat. No. 5,580,465 and U.S.Pat. No. 4,618,533.

Also known in the art are composite leukocyte filters comprisingpolymeric fibres and solid particles to increase the total surface areaof the filtering material.

U.S. Pat. No. 5,454,946 describes a filter material for filteringleukocytes comprising a web made by interlocked matrix fibres, mainlyconsisting of glass fibres and fibrillated particles of textile fibrematerial disposed within the spaces of the matrix. A thermoplasticbinder is disposed at the cross-over portion of the matrix fibres. Thefibrillated particles do not have adsorption properties and are notporous in nature.

U.S. Pat. No. 6,337,026 also describes filtration media for leukocytedepletion of the type described in U.S. Pat. No. 5,454,946 wherein theparticles have a very high specific surface area of at least 100 m²/gand the weight ratio of the particles to the matrix fibres is less than100.

US 2001/00 09756 A1 describes a device for reducing the concentration oflow molecular weight compounds in biological composition comprising aninert matrix containing adsorbent particles. The compounds which can beremoved, which have molecular weight from 100 g/mol to about 30000 g/molinclude pathogen-inactivating agents such as photoactivation products,aminoacridines, organic dyes and phenothiazines. Such devices are notdescribed for use in leukocyte depletion.

The present invention provides a filtering material and filter deviceswhich in addition to being able to remove low molecular weight compoundsfrom blood products and whole blood or blood components also achievehigh efficiency in leukocyte removal.

The subject matter of the invention is defined in the appended claims.

The filter device, which constitute a subject of the invention, has aporous element comprising at least one fibrous web having a pore sizesuitable for leukocyte removal. The said web comprises fibres of ahydrophobic polymer which are at least partially coated with ahydrophilic polymer suitable to increase the Critical Wetting SurfaceTension (CWST) or hydrophilicity of said hydrophobic polymer. Suitablehydrophobic polymers include polyolefins, such as polyethylene andpolypropylene, polyamides, polyaramides, polyacrylics,polyacrilonitriles, cellulose acetate, polyvinylidenefluoride andpolyesters. The preferred polymer is polybutylenterephthalate (PBT).

The fibre diameter of the non woven web is generally in the range offrom 0.01 micron to 5 micron.

The preferred technique for producing the fibres of the non woven randomweb is by melt blowing technology. By that technology, the intrinsicporosity and the fibre diameter distribution of the fabric can bedetermined by the process parameters such as spinneret characteristicsand setting, D.C.D. (Distance Conveyor to Die), hot air and polymerthroughput, process temperature, suction and positioning (e.g.inclination) of the collector.

The adsorbent particles are bonded to the fibre matrix so that they arenot released under either static or flow conditions in contact withbiologic fluids. Adsorbent microparticles for use in the filter of theinvention include microparticles made of a biocompatible material or atleast partially coated with a biocompatible material. Adsorbentparticles or beads, suitable for removing toxicants from blood or plasmaare known in the art. They include polymeric materials such aspolyacrylics, polyesters, polyamides, polyacrylamides and polystyrenecopolymers; a preferred material is polystyrene-divinylbenzene (DVB) orpolyamide. Also active charcoal could be used. The particles or beadsdiameter may vary in a wide range generally of from 0.1 to 200 micron.However, it is particularly preferred the use of particles having a meandiameter lower than 30 μm. Also contemplated within the scope of theinvention is the use of microparticles having an internal microporositywith a specific surface area higher than 200 m²/g up to about 800 m²/gor more.

The hydrophilic polymer which is used to enhance the hydrophilicity ofthe hydrophobic fibres is preferably selected from co-polymers obtainedby polymerization of vinylacetate (VA) and vynilpyrrolidone (VP) in adifferent mole ratio, such as VA/VP=50÷4.

The adsorbent particles may be bonded to the fibre surface by means ofseveral methods known in the art e.g. by heat treatment, inclusionmethods and coating. However, according to the invention, the preferredmethod is by coating with the use of the same hydrophilic polymer whichis used to enhance the hydrophilicity of the fibre material. Accordingto the preferred method a porous web of hydrophobic fibres (preferablyPBT) is impregnated or soaked with a solution of the selectedhydrophilic polymer, including a solvent for the said polymer (e.g. analcoholic solvent) solvent and in suspension said adsorbent particles.By properly selecting the concentration of the hydrophilic polymer inthe solution and the amount of particles in the solution it is possibleto achieve, upon drying of the thus impregnating web, a filteringmaterial wherein the adsorbent particles are bonded to the fibre surfaceand the fibre surface as well as the particle surface is at leastpartially coated with the hydrophilic polymer. It as been found thatsuch a coating does not impair the adsorption properties of theadsorbent particles. In this method, preferably, the hydrophilicpolymer, which as stated before is preferably polyvinylpyrrolidone, isused in the impregnating solution with a concentration of from 0.1 to 5%by weight and the adsorbent particles, which are preferably made ofpolystyrene-DVB or polyamide are added to the solution in the amount offrom 0.5 to 10% by weight, preferably 0.1 to 100% by weight.

Typically, the amount of adsorbent particles bonded to the fibre web isin the range of from 0.01 to 0.5 g per gram of web, preferably from 0.1to 0.5 g/g.

The overall porosity of the filter material of the invention is due tothe diameter of the fibre, to the size of the microparticles and to thedistribution and the concentration of the microparticles. Then, throughthe use of the microparticles it is possible to reduce the porosity ofthe material in order to increase the leukodepletion efficiency of thefilter (without the need to drastically modify the originalcharacteristics of the fibres material (e.g. the thickness)) and henceto optimize its final profile.

With the use of the adsorbent particles and particularly ofpolystyrene-DVB or polyamide particles with a high surface area, thefiltering material of the invention also allows to remove low molecularweight substances from blood and blood products such as dyes andphotoactive molecules such as viricide-potentiating agents, such asmetylene blue, acrydinyl derivatives, psoralen and psoralen derivatives.

EXAMPLE 1 Comparison Between a Filter Made with the New Material and aFilter Made with Conventional Material

Whole blood (WB) filters with the new filter material were compared withfilters made with conventional filter material.

The filter material according to the invention was made of a non wovenweb of PBT fibres coated with polyvinylpirrolidone and including bondedpolyamide particles having a mean diameter of about 12 μm and with aparticle content of about 0.4 g/g of web.

Each filter was made with 3.0 layers of this new filter material.

The conventional filter material was a non woven web of PBT coated withthe same polyvinylpyrrolidone solution used for the new filter material.

WB filters with the conventional filter material were made with 40layers in one case and with 30 layers in the other one.

Whole blood (range 450-550 ml) was collected from random donors in a PVCbag with 70 ml of CPD. All whole-blood donations were cooled to 20-24°C. under 1,4 butane-diol plates. The filtration was performed bygravity.

WBCs in the filtered blood were counted in a Nageotte hemocytometer.

The results obtained are summarised in the following table:

Filter New filter Conventional Conventional material filter materialfilter material 30 layers 40 layers 30 layers WBCs in 80000 ± 70000100000 ± 80000 900000 ± 750000 filtered blood

These experimental results show that the new filter material has higherefficiency in leukodepletion and it allows to obtain the same results ofconventional filters with less material.

EXAMPLE 2 Removal of Acridine Derivatives from RCC

A filter was made with the new filter material as described in example 1with the use of PS-DVB microspheres in the amount of 0.4 g/g of web.

The mean diameter of microspheres was 35 micron and the surface area was900 m²/g. Thirty layers of this material were used to make a filter.

An acridine derivatives was added to a bag of RCC with SAG-M (Vol.=ml270) in order to obtain a concentration of the acridine derivatives of200 micromol.

The filtration was performed by gravity and the acridine derivativescontent after the filtration was less then 1 micromolar.

With a conventional filter (40 layers) there was no removal of theacridine derivatives.

1. A filter device for the depletion of the leukocyte content from bloodproducts comprising: a porous element comprising at least one fibrousweb having a pore size suitable for leukocyte removal, said webcomprising fibres of a hydrophobic polymer coated with a hydrophilicpolymer suitable to enhance the CWST of said hydrophobic polymer,characterised in that said web further includes adsorbent particleshaving a mean diameter lower than 30 μm, said particles being bonded tosaid fibres by means of said hydrophilic polymer coating said fibres. 2.The filter device according to claim 1, wherein said web is obtainableby soaking (impregnating) a web of fibres of said hydrophobic polymerwith a solution of said hydrophilic polymer including in suspension saidadsorbent particles.
 3. The filter device according to claim 2, whereinsaid solution comprises from 0.1 to 10% by wt. of said particles.
 4. Thefilter device according to claim 1, wherein said hydrophilic coatingpolymer is selected from co-polymers obtained by polymerization ofvinylacetate and vinylpyrrolidone.
 5. The filter device according toclaim 1, wherein said absorbent particles are made from a materialselected from the group consisting of acrylic polymers, polyesters,polyamides, polyacrylamides, active charcoal andpolystyrene-divinylbenzene.
 6. The filter device according to claim 1,wherein said hydrophobic polymer is selected from the group consistingof polyethylene, polypropylene, cellulose acetate, polyamides, acrylicpolymers, polyacrylonitriles, polyvinylidene fluoride, polyaramides andpolyesters, particularly polybutylenterephthalate.
 7. The filter deviceaccording to, claim 1 wherein said web comprises an amount of particlesin the range from 0.01 to 0.5 g/g of the fibre web material.
 8. Thefilter device according to claim 1 wherein the hydrophobic polymer ispolibutylenterephthalate and the adsorbent particles are made ofpolyamide or polystyrene-divinylbenzene polymer and are bonded to thehydrophobic fibres by means of polyvinylpyrrolidone at least partiallycoating said fibres.
 9. The method for removing substances from bloodproducts comprising feeding said blood products through a filteraccording to claim
 1. 10. The blood purification device comprising afilter according to claim
 1. 11. The blood purification device accordingto claim 10 consisting of blood bag device for the separation of bloodinto leukocyte depleted blood components, comprising a first bagconnected, in fluid flow communication, with a second bag through afilter.